The long-term goal of this proposal is to develop a mouse model for Primary Hyperoxaluria Type II (PH2). PH2 is a monogenic disease that results from a genetic defect in pathways that lead to oxalate formation. Patients with this disease excrete excessive amounts of oxalate in their urine. Overproduction of oxalate can lead to calcium oxalate stone disease, nephrocalcinosis, end-stage renal failure, and systemic oxalosis. There are currently no effective therapeutic treatments for PH2. We have recently identified the molecular basis for PH2 in humans. Our data demonstrate that patients with PH2 have inactivating mutations in both alleles of the gene encoding glyoxylate reductase/hydroxypyruvate reductase (GRHPR). This is consistent with considerable biochemical evidence that suggests that the disease is a result of the lack of the GRHPR enzyme. Our data are also consistent with the hypothesis that PH2 is a monogenic disease with an autosomal recessive pattern of inheritance. Prior to our work it was thought that the source of oxalate in PH2 patients is primarily the liver and this has spurred suggestions that liver transplantation may be an effective therapeutic strategy. Our studies have demonstrated that the GRHPR gene is expressed in a wide variety of tissues and suggest that the source of oxalate in PH2 patients may not be restricted to the liver. The hypothesis of this proposal is that deletion of the GRHPR gene in mice will lead to hyperoxaluria. To test this hypothesis we will create a strain of mice containing a deletion in the GRHPR gene. In Specific Aim 1 we will generate ES cells with a targeted disruption of the mGRHPR gene. In Specific Aim 2 we will evaluate the phenotype of the GRHPR -/- mice. In Specific Aim 3 we will determine the tissue distribution of GRHPR expression and the tissue oxalate content in GRHPR -/- mice. A GRHPR knockout mouse that exhibits hyperoxaluria will be useful for the future development of novel therapeutic strategies for PH2 and for elucidating the tissue source(s) of oxalate in PH2 patients.